The long-term objective of this application is to develop criteria for the identification of families with patterns of longevity that are largely genetically determined. Such criteria could greatly facilitate future efforts to map and clone genes contributing to human longevity. Identification of these genes may lead to the discovery of the fundamental molecular mechanisms of senescence, and to the development of therapeutic interventions that simultaneously promote longevity and postpone the onset of multiple age-related diseases and disabilities. The Specific Aims of the Research Plan are I) Test the hypothesis that mitochondrial inheritance contributes to longevity, and 2) Develop criteria to select sib pairs suitable for genetic linkage studies of longevity. Both aims will be carried out by analyzing mortality and family relationship data in the Utah Population Database, a large genealogy containing records on approximately 1.2 million individuals from 170,000 families. Essentially all of one's mitochondria are inherited from one's mother. In a pedigree all individuals who are related by an uninterrupted chain of gene transmission through females lie within a single maternal lineage and share their mitochondrial inheritance. The hypothesis that mitochondrial genetic variants can predispose to longevity predicts that the incidence of longevity among individuals from the same maternal lineage as an extremely long- lived proband will be significantly higher than the incidence of longevity among individuals equally related to that proband with regard to the inheritance of nuclear genes, but who derive their mitochondria from other maternal lineages. To find families suitable for sib pair linkage studies to map nuclear genes contributing to longevity, families will be ascertained on the basis of one or more of the family members meeting various selection criteria relevant to longevity. The frequency of longevity among siblings who were not the basis of ascertaining the family will then be compared to the frequency of longevity in the general population to obtain a relative risk, lambda-s, of longevity. To maximize power to detect linkage, one would like to find family selection criteria that 1) yield a high lambda-s and 2) are met by large numbers of sib pairs in the population that is available for sampling. This proposal addresses the Biodemography of Aging, an area targeted by this research grant program.